Multiple system atrophy (MSA) is defined as an adult-onset, sporadic, rapidly progressive, multisystem, neurodegenerative fatal disease of undetermined etiology, characterized clinically by varying severity of parkinsonian features; cerebellar, autonomic, and urogenital dysfunction; and corticospinal disorders. Neuropathological hallmarks of MSA are cell loss in the striatonigral and olivopontocerebellar structures of the brain and spinal cord accompanied by profuse, distinctive glia cytoplasmic inclusions (GCIs) formed by fibrillized alpha-synuclein proteins (defined as primary alpha-synucleinopathy). (See Etiology and Pathophysiology, History and Physical Examination, and Workup.)[1]
A consensus statement by the American Autonomic Society and American Academy of Neurology in 2007[2] categorized MSA in MSA-P with predominant parkinsonism and MSA-P with dominant cerebellar features (MSA-C). (See Categories of MSA below.)
The concept of MSA as a unitary diagnosis encompassing several clinical syndromes has a long history. The first cases of MSA were presented as olivopontocerebellar atrophy (OPCA) about a century ago. The Shy-Drager syndrome with features of parkinsonism and autonomic failure with OH was described in 1960. The term MSA was introduced to unify different forms of MSA in 1996. The discovery of GCIs and alpha-synuclein immunostaining as a sensitive marker of MSA were major milestones in the definition of MSA as a clinicopathologic entity. (See Table 1, below).[3]
Table 1. Historical Milestones in the Definition of Terms for MSA
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A consensus conference in 2007[6] simplified the older definition of MSA—as determined by the Consensus Committee representing the American Autonomic Society and the American Academy of Neurology in 1996 and 1998[2] —and incorporated current knowledge for a better assessment of the disease.[7]
Categories of MSA
The 2 categories of MSA are as follows:
MSA with predominant parkinsonism (MSA-P) - Extrapyramidal features predominate; the term striatonigral degeneration, parkinsonian variant is sometimes used
MSA with cerebellar features (MSA-C) - Cerebellar ataxia predominates; it is sometimes termed sporadic olivopontocerebellar atrophy
The designation of MSA-P or MSA-C depends on the dominant feature at the time of evaluation, which can change with time.
Shy-Drager syndrome
When autonomic failure predominates, MSA was sometimes termed Shy-Drager syndrome (not defined in the present consensus anymore).
Characteristics of MSA
Features indicating the presence of MSA (tables 2a and 2b) or of another disorder (Table 3) are described below. (Corticospinal tract dysfunction with extensor plantar response with hyperreflexia [pyramidal sign] is not used to categorize MSA.) (See DDx.)
Table 2a. Main Features for the Diagnosis of MSA
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Table 2b. Additional Features for the Diagnosis of Possible MSA*
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Table 3. Characteristics That Do Not Support the Diagnosis of MSA
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Levels of certainty of MSA
MSA can be ascertained as possible, probable, or definite MSA (see Table 4, below), based on autonomic and urogenital features, on the presence of parkinsonism, and on cerebellar dysfunction, as well as on additional features (see tables 2a and 2b, above).
Only pathologic findings of high density of alpha-synuclein-positive glial cytoplasmic inclusions (GCIs) and degenerative changes in the striatonigral or olivopontocerebellar pathways can definitively confirm the diagnosis of MSA. (See Workup.)
Table 4. Diagnostic Categories of MSA
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Red flags supporting the diagnosis of MSA include the following:
Orofacial dystonia
Disproportionate antecollis
Severe anterior flexion of the spine (camptocormia)
Severe lateral flexion of the spine (Pisa syndrome)
Contractures of hands and feet
Inspiratory sighs
Severe dysphonia
Severe dysarthria
New or increased snoring
Cold hands and feet
Pathologic laughter or crying
Jerky myoclonic postural/action tremor
Patient education
A variety of resources are available for patient education. These include the Web sites of the Multiple System Atrophy Coalitions, Autonomic Disorder Consortium of the Clinical Rare Diseases Research Network, and Vanderbilt Autonomic Dysfunction Center.
MSA is characterized by progressive loss of neuronal and oligodendroglial cells in numerous sites in the central nervous system (CNS). The cause of MSA remains unclear, although a history of trauma has been suggested. Pesticide exposure as a causative factor in MSA has been suggested but has not been confirmed statistically.[8] Autoimmune mechanisms have also been suggested as potential causes of MSA, but evidence for these is weak.
There is some evidence of genetic predispositions in Japanese cohorts. Autosomal recessive inheritance[9] and genetic alterations with abnormal expansion of 1 allele of the SCA type 3 gene has been reported.[10] Single nucleotide polymorphisms (SNPs) at the SNCA locus coding for alpha-synuclide have been identified. G51D mutation in the SNCA locus has been described, but a connection between SCNA locus and MSA disease could not be confirmed. Associations with COQ2 and C9orf72 have been reported.[11, 12]
Researchers initially assumed that gray-matter damage caused MSA. However, the discovery of oligodendroglial glial cytoplasmic inclusions (GCIs) (see Table 8) indicated that damage primarily affects the white matter. The chronic alterations in glial cells may impair trophic function between oligodendrocytes and axons and cause secondary neuronal damage. Whether the inclusions represent primary lesions or nonspecific secondary markers of cellular injury remains unknown. In addition to the GCIs, extensive myelin degeneration occurs in the brain. Changes in myelin may play an important role in the pathogenesis of MSA. The clinical symptoms of MSA correlate with cell loss in different CNS sites. (See Table 5, below.)
The prevalence of MSA is reported to be between 3.4-4.9 cases per 100,000 population. The estimated mean incidence is 0.6-0.7 cases per 100,000 person-years. MSA meets orphan disease status.[14, 15]
Many patients do not receive the correct diagnosis during their lifetime because of the difficulty in differentiating MSA from other disorders (eg, Parkinson disease, pure autonomic failure [PAF], other rare movement disorders). About 29-33% of patients with isolated late-onset cerebellar ataxia and 8-10% of patients with parkinsonism will develop MSA. Therefore, a higher prevalence than that estimated can be assumed.
International occurrence
In the European Union (EU), the prevalence rates show 4-5 cases per 100,000 persons. The incidence rate is about 0.6 cases per 100,000 persons per year.[16]
In the United Kingdom, the crude prevalence of MSA, including all probable and possible cases, is 3.3 per 100,000 population.[17]
In Iceland, the incidence is 0.6 per 100,000 and prevalence is 3.1 per 100,000.[18]
In Japan, the prevalence is 13.1 per 100,000 individuals. The mean annual incidence is 0.68.[19]
Race-, sex-, and age-related demographics
MSA has been encountered in Caucasian, African, and Asian populations. In Western countries, MSA-P predominates, occurring in 66-82% of patients. In Eastern countries (e.g., Japan), MSA-C is common, occurring in 67% of patients.
The disease more often affects men than women. The female-to-male ratio is around 1:2. (A ratio of 1:3-9 has also been reported.) However, the early and easy diagnosis of impotence may have led to the male statistical predominance of MSA. The mean age at onset in MSA is 52.5-55 years. The disease progresses over intervals of 1-18 years.
Patients with MSA have a poor prognosis. The disease progresses rapidly. Median survivals of 6.2-9.5 years from the onset of first symptoms have been reported since the late 20th century. No current therapeutic modality reverses or halts the progress of this disease. MSA-P and MSA-C have the same survival times, but MSA-P shows more rapid dysfunctional progression.
An older age at onset has been associated with shorter duration of survival in MSA. The overall striatonigral cell loss is correlated with the severity of disease at the time of death.
Bronchopneumonia (48%) and sudden death (21%) are common terminal conditions in MSA. Urinary dysfunction in MSA often leads to lower urinary tract infections (UTIs); more than 50% of patients with MSA suffer from recurrent lower UTIs and a significant number die of related complications.[20]
Most patients with multiple system atrophy (MSA) develop the disease when they are older than 40 years (average 52-55y), and they experience fast progression. Usually autonomic and/or urinary dysfunction develops first. Patients with MSA may have parkinsonian symptoms with poor or nonsustained response to levodopa therapy. Only 30% of MSA-P patients have an initial transient improvement. About 90% of patients are nonresponsive to long-term levodopa therapy.
Typically, 60% of patients experience objective decline in motor function within 1 year. Motor impairment can be caused by cerebellar dysfunction. Corticospinal tract dysfunction also can occur but is not often a major symptomatic feature of MSA. Table 2a provides an overview of the clinical domains and their main features. More details are described in subsequent sections.[21]
Autonomic and/or urinary dysfunction
Autonomic symptoms are the initial feature in 41-74% of patients with MSA; these symptoms ultimately develop in 97% of patients. Genitourinary dysfunction is the most frequent initial complaint in women, and erectile dysfunction is the most frequent initial complaint in men.
Severe orthostatic hypotension
Severe orthostatic hypotension is defined as a reduction in systolic blood pressure (BP) of at least 30mm Hg or in diastolic BP of at least 15mm Hg, within 3 minutes of standing from a previous 3-minute interval in the recumbent position. This form of hypotension is common in MSA, being present in at least 68% of patients. Most patients do not respond with an adequate heart rate increase. The definition of severe orthostatic BP fall as a diagnostic criterion for MSA is stricter than the definition of orthostatic hypotension as a physical finding as defined by the American Autonomic Society.[22]
Symptoms associated with orthostatic hypotension include the following:
Light-headedness
Dizziness
Dimming of vision
Head, neck, or shoulder pain
Altered mentation
Weakness - Especially of the legs
Fatigue
Yawning
Slurred speech
Syncope
Some patients have fewer orthostatic symptoms. In 51% of patients with MSA, syncope is reported at least once. In 18% of patients with severe hypotension, more than 1 syncopal episode is documented. Because of dysautonomia-mediated baroreflex impairment and consequent debuffering, patients respond in an exaggerated fashion to drugs that raise or lower their BP.
Orthostatic hypotension must be distinguished from postural tachycardia syndrome, which is defined as an increase in heart rate of greater than 30 beats per minute (bpm) and maintained BP (absence of orthostatic hypotension).
Postprandial hypotension
Patients are also susceptible to postprandial hypotension. Altered venous capacitance and baroreflex dysfunction have been reported as a cause.[23]
Supine hypertension
Approximately 60% of patients with MSA have orthostatic hypotension and supine hypertension. The supine hypertension is sometimes severe (>190/110mm Hg) and complicates the treatment of orthostatic hypotension.
Parkinsonism
Parkinsonism can be the initial feature in 46% of patients with MSA with predominant parkinsonism (MSA-P); it ultimately develops in 91% of these MSA-P patients. Although akinesia and rigidity predominate, tremor is present at rest in 29% of patients; however, a classic pill-rolling parkinsonian rest tremor is recorded in only 8-9%. Patients with MSA-P have a poor response to levodopa.
About 28-29% of patients have a good or even excellent levodopa response early in their disease. However, only 13% maintain this response. Patients with early onset (at < 49 y) MSA-P tend to have a good levodopa response.
Patients sometimes complain of stiffness, clumsiness, or a change in their handwriting at the onset of the disease.
Cerebellar dysfunction
Cerebellar symptoms or signs are the only initial feature in 5% of MSA patients. MSA with cerebellar features (MSA-C) most commonly causes gait and limb ataxia; tremor, pyramidal signs, and myoclonus are less common findings.
Additional symptoms
Other symptoms of MSA are based on mixed dysfunction. When the disorder results in nonautonomic features, imbalance caused by cerebellar or extrapyramidal abnormalities is the most common feature.
If the cerebellar, extrapyramidal, and pyramidal systems are involved, the movement disorder is usually the most profound disability.
Vocal cord paralysis may lead to hoarseness and stridor. A neurogenic and obstructive mixed form of sleep apnea can occur.
Multiple system atrophy (MSA) is a difficult diagnosis, especially early in the clinical course, and the initial physician often misdiagnoses the condition. The most common initial diagnosis is idiopathic Parkinson disease.
The diagnosis of MSA is based mainly on clinical features (see tables 2a, 2b, 3, and 4). The presence of MSA can be definitively established only on postmortem examination. MSA is confirmed by the presence of a high density of glial cytoplasmic inclusions (GCIs) in association with degenerative changes in the striatonigral and olivopontocerebellar pathway.
In a patient with autonomic failure and orthostatic hypotension, the combination of a normal supine norepinephrine level that does not rise significantly with upright position suggests MSA.
Autonomic function testing
This can used to evaluate the distribution and severity of parasympathetic and sympathetic dysfunction. Findings include the following:
Diminished respiratory sinus arrhythmia
Abnormal response to Valsalva maneuver (no BP recovery in late phase II and/or no overshoot in phase IV, reduced Valsalva ratio for heart rate)
Reduced response to isometric exercise (handgrip)
Diminished response to cold pressor test
Sphincter electromyography (EMG)
Sphincter electromyography (EMG) can be used to detect hyperreflexia of the detrusor.
Measurement of urine residual volume by ultrasonography
Incomplete bladder emptying of greater than 100ml can be detected through ultrasonography.
Detrusor contractions
Impaired detrusor contractility is the pathognomonic urodynamic finding that distinguishes MSA from PD.[30]
Scintigraphy
Scintigraphy with iodine-123 metaiodobenzylguanidine (123 I MIBG) appears to be a useful tool for differentiation between Parkinson disease and MSA early after onset of autonomic dysfunction (90% sensitivity, 95% specificity).
Patients with Parkinson disease have significantly lower cardiac123 I MIBG uptake than do some patients with MSA and controls. However, studies have shown imperfect reliability.[31, 32]
Brain images may be normal in MSA. However, olivopontocerebellar atrophy (OPCA), cerebellar atrophy, and the putaminal lesions of striatonigral degeneration are often detected using MRI techniques. The slight hyperintensity of the lateral margin of the putamen on T2-weighted MRI is a characteristic finding in patients with MSA involving the extrapyramidal system.[33]
Expected MRI findings in MSA are as follows:
Atrophy of cerebellum and brainstem in OPCA and striatonigral degeneration (SND)
No vascular damage
No multi-infarct pattern in brain
No other lesions
Hyperintensity in the pons, peduncles, and cerebellum on T2-weighted and proton density–weighted MRI scans
Slitlike hyperintensity on T2-weighted and proton density–weighted MRI scans; a cruciform hyperintensity in the pons on T2-weighted MRI, known as the hot cross bun sign, is diagnostically helpful, but it is not specific to MSA.[34]
In addition, MRI and proton MR studies can be used to exclude other conditions, such as multi-infarct syndromes.
Trace (D)
A study using diffusion-weighted MRI showed that patients with MSA with predominant parkinsonism (MSA-P) had significantly higher Trace (D) values in the entire and anterior putamen, whereas patients with MSA with cerebellar features (MSA-C) had significantly higher Trace (D) values in the cerebellum and middle cerebellar peduncle. Furthermore, increased disease duration correlated significantly with increased Trace (D) values in the pons of patients with MSA-P and in the cerebellum and middle cerebellar peduncle of patients with MSA-C.[35]
MSA can be differentiated from Parkinson disease with the use of FDG-PET scanning. The caudate-putamen index, which is calculated using a formula based on the difference in the uptakes in the caudate and putamen divided by the caudate uptake, is lower in patients with MSA than in patients with Parkinson disease.[36]
Expected findings in MSA are as follows:
Reduced putaminal FDG uptake
Reduced [11 C]raclopride and [11 C]diprenorphine levels
Reduced cerebellar glucose metabolism in OPCA
Absence of parkinsonian features but evidence of striatonigral dopaminergic denervation may point to MSA.
Neuropathologic changes in MSA consist of the development of a high density of GCIs in association with degenerative changes in some or all of the following structures (Table 5 provides an overview of the clinicopathologic correlation):
Putamen
Caudate nucleus
Globus pallidus
Thalamus
Subthalamic nucleus
Substantia nigra
Locus ceruleus
Dorsal vagal nucleus
Vestibular nuclei
Pontine nuclei
Inferior olives
Pontine nuclei
Cerebellar Purkinje cells
Autonomic nuclei of the brainstem
Intermediolateral cell columns
Anterior horn cells
Onuf nuclei in the spinal cord and pyramidal tracts
GCIs, which can be stained using the Gallyas silver technique, range from sickle shaped to flame shaped to ovoid, on occasion, superficially resembling neurofibrillary tangles. GCIs are loosely aggregated filaments with cross-sectional diameters of 20-30 nm. These filaments often entrap cytoplasmic organelles (eg, mitochondria, secretory vesicles), have no limiting membrane, and have tubular profiles and electrodense granules along much of their lengths. GCIs are ubiquitin-positive, tau-positive, and alpha-synuclein ̶ positive oligodendroglial inclusions. They are different from Lewy bodies and neurofibrillary structures in Alzheimer disease. (See Table 8, below.)
Table 8. Differences Between GCIs in MSA and Other Pathologic Inclusions and Structures
The cause of multiple system atrophy (MSA) remains unknown, and no current therapy can reverse or halt progression of the disease. The extrapyramidal and cerebellar aspects of the disease are debilitating and difficult to treat.
Nonpharmacologic treatment
See the list below:
Constipation - A high-fiber diet, bulk laxative, lactulose, and suppositories can prevent constipation
Stridor - Speech therapy is often useful to improve swallowing and communication
Deconditioning - Physical therapy and an aquatic exercise program (hypotension does not occur while patients are in water) prevent physical deconditioning of the patient unless the movement disorder aspect of the illness so impairs balance that this is not advisable
Urinary incontinence - Intermittent self catheterization or suprapubic or urethral catheterization can improve symptoms of urinary incontinence
Falls - As the disease progresses, the risk of falls increases; proper gait instruction and precautions are critical to prevent falls and resultant injury
Pharmacologic treatment
Drug therapy is directed mainly toward alleviation of symptoms of the movement disorder and orthostatic hypotension. Urinary incontinence, constipation, erectile dysfunction, and supine hypertension can also be addressed through pharmacologic therapy. (See Table 9.)
Surgical care
An atrial pacemaker may be used in patients with profound bradycardia in addition to orthostatic hypotension as a means of preventing the hypotension. However, this treatment is rarely undertaken and is rarely helpful.
Consider tracheostomy with the utmost care for intermittent respiratory stridor. Cricopharyngeal myotomy or gastrostomy has been used in patients with severe dysphagia, but its value is uncertain.
Consultations
Physical therapists, occupational therapists, speech therapists, and social workers can offer considerable practical help.
Diet
An essentially normal diet is recommended, with the following guidelines:
Increased salt and fluid intake maintains plasma volume
Small, frequent meals may help patients for whom postprandial hypotension is a significant problem
A high-fiber diet, bulk laxatives, and suppositories prevent constipation
Activity
Exercise of muscles of the lower extremities and abdomen, water aerobics at hip level (not swimming, as it causes polyuria), and postural training, in combination with drug therapy, are useful.
Inpatient evaluation and tailoring of therapy are often important. However, if patients are restricted to bedrest, their functional mobility can decrease rapidly. Therefore, initiate physical therapy if the patient must remain in the hospital for longer than 2 days.
Nonpharmacologic Treatment of Hypotension and Hypertension
Orthostatic hypotension
The earliest symptom that brings patients to medical attention usually is orthostatic hypotension. Orthostatic hypotension leads to curtailing of physical activity, with all of the problems of deconditioning that consequently occur. Without an adequate upright BP, keeping patients active and on an exercise regimen is extremely difficult; therefore, management of orthostatic hypotension is one of the major tasks in the treatment of patients with MSA.
Mechanical maneuvers, such as leg-crossing, squatting, abdominal compression, bending forward, and placing 1 foot on a chair, can be effective in preventing episodes of orthostatic hypotension. Wearing an external support garment that comes to the waist improves venous return and preload to the heart during standing but loses effectiveness if the patient also wears it while supine. Increased salt and fluid intake and tilted sleeping with the head elevated increase the circulatory plasma volume.
Postprandial hypotension
Small, frequent meals attenuate BP drop after eating. Intake of water half an hour before meals or drinking coffee can counteract postprandial hypotension.
Supine hypertension
The management of patients with orthostatic hypotension and supine hypertension can be challenging, but adequate BP control is often achieved with the following treatment strategy:
Use of over-the-counter medication with pressor effects
Avoidance of fluid intake at bedtime
Not using elastic stockings when supine
Not using pressor agents before bedtime
Raising the head of the bed 6-9 inches
Resting on a semirecumbent chair with feet on the floor during the day
As previously mentioned, pharmacologic therapy for multiple system atrophy (MSA) is directed mainly toward alleviation of symptoms of the movement disorder and orthostatic hypotension (see Table 9, below). Medications can also be used to treat urinary incontinence, constipation, erectile dysfunction, and supine hypertension. In recent years, neuroprotective therapy has been successfully applied in the mouse model.[37] But studies in humans (e.g., rifampicin rasagiline) did not show beneficial effects on slowing down the disease.[38, 39] Transgenic MSA mouse models do not have the same human phenotype but may be the best choice to explore new therapies.[40]
Medical therapy of movement disorder
The movement-disorder component of MSA is usually treated with levodopa, dopaminergic agonists, anticholinergic agents, or amantadine, but results are rarely as favorable in MSA as in classic Parkinson disease.
Drugs that now are not commonly used in patients with MSA include nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, somatostatin analogues, and caffeine.
Medical therapy of orthostatic hypotension
Many agents have been advocated for the management of orthostatic hypotension. Table 9, below, shows some of the most widely used drugs. However, drug therapy of orthostatic hypotension is limited by supine hypertension, which affects about 60% of patients with MSA.[41]
In February 2014, droxidopa was approved by the FDA for the treatment of orthostatic hypotension. It is a synthetic amino precursor prodrug and is converted to norepinephrine.[42]
Water is a uniquely powerful pressor agent in the management of orthostatic hypotension in patients with MSA. It acts by increasing sympathetic activity. On average, 16 ounces of water will raise BP about 30 mm Hg. Patients may understandably be skeptical that something so commonplace could help raise their BP, so it does require patient education. No other beverage (not juice or coffee or even Gatorade) is as good as a pressor agent as water in patients with autonomic dysfunction. Its major limitations are a short (1-hour) half-life and increased urination (inconvenient when autonomic impairment makes urination difficult).
Patients should drink 16 ounces of water on awakening each morning, even before they get out of bed. Patients should learn to use water prophylactically; they will be able to do much more in the hour after ingesting water than at other times. A repeat dosing midmorning or at lunch and at midafternoon may give the patient additional capacity for activity during this part of the day. Conversely, since patients with autonomic failure commonly have supine hypertension, we discourage them from drinking large amounts of water within the 2 hours prior to bedtime, although we allow them to drink when they are thirsty.
Table 9. Drugs Used to Manage Orthostatic Hypotension in MSA
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Medical therapy of supine hypertension
The presence of supine hypertension can complicate the pharmacologic management of patients with MSA, but a rational approach to its treatment is often successful. Simply avoiding the supine position is often enough to control hypertension during the day. Treatment of supine hypertension is required at night. Elevating the head of the bed is useful but rarely sufficient. Short-acting vasodilators are effective in controlling hypertension.
The management of patients with orthostatic hypotension and supine hypertension can be challenging, but adequate BP control is often achieved by combining the nonpharmacologic approach, as previously described, with the following medications:
Clinical Context:
In this combination, levodopa is administered with a dopa decarboxylase inhibitor. When levodopa is administered alone, it is largely decarboxylated by the intestinal mucosa or other peripheral sites rich in monoamine oxidase (MAO), and little reaches the cerebral circulation and CNS.
Patients with MSA may have an initial response to levodopa, but this response usually diminishes over time. Withdrawal of levodopa can cause a patient's condition to deteriorate, but this is much more prominent in Parkinson disease than in MSA. In modern practice, levodopa is administered in combination with a dopa decarboxylase inhibitor.
These agents are used as alternatives to levodopa therapy in the late phase of the movement disorder. They selectively act on different subtypes of dopamine receptors throughout the brain. The mechanism through which dopaminergic agonists act is independent of the functional capacities of the striatonigral neurons and may be more effective than those of other drugs.
Clinical Context:
Tolterodine is a competitive muscarinic receptor antagonist for overactive bladder. It differs from other anticholinergics by being selective for the urinary bladder over the salivary glands. Tolterodine has high specificity for muscarinic receptors and has minimal activity or affinity for other neurotransmitter receptors and other potential targets (eg, calcium channels).
When detrusor hyperreflexia is the cause of a patient's urinary incontinence, peripherally acting anticholinergic agents (eg, oxybutynin chloride [Ditropan], tolterodine [Detrol], propantheline [Pro-Banthine]) can be applied.
Clinical Context:
Erythromycin is a macrolide antibiotic that duplicates the action of motilin. By binding to and activating motilin receptors, it is responsible for migrating motor complex activity. IV administration enhances the emptying rate of liquids and solids. The effect can also be seen with oral erythromycin. The enteric-coated form may be the most tolerable. However, erythromycin's benefit as a prokinetic agent is usually marginal in MSA.
If a special bulk-forming diet fails, lactulose occasionally is helpful. In rare cases, cisapride (Propulsid) may promote bowel movements, but this agent has been removed from the US market because of risk of cardiac rhythm disturbances.
MSA may respond to yohimbine with BP elevation, but male erectile dysfunction only occasionally improves. Yohimbine (Yohimex, Yocon) should be given at a dose of 5.4 mg 3 times a day for the purposes of blood pressure elevation. Yohimbine has a very limited ability to improve erectile dysfunction in MSA and can dangerously elevate blood pressure when given with acetylcholinesterase inhibitors such as pyridostigmine. If adverse effects are a problem, the dose can be reduced to half a tablet 3 times a day and gradually increased to 1 tablet 3 times a day. The effect of sildenafil (Viagra) has not been determined in patients with autonomic failure. Other approaches include the use of mechanical devices, pumps, penile prostheses, or implants.
Clinical Context:
Fludrocortisone has been a mainstay of pressor therapy for the last 50 years. It is a powerful mineralocorticoid that is largely devoid of a glucocorticoid effect when it is administered in low to moderate doses (0.1-0.3 mg). This agent can initially increase blood volume, which tends to normalize after the first week. Most patients gradually (over 2 wk) gain weight (usually 5-8 lb), with mild ankle edema occurring as a result of sodium retention, primarily in the extravascular compartment.
Much of the drug's benefit depends on support from tissue edema to the venous capacitance bed in the lower abdomen and extremities. With edema, the venous bed accommodates only a low volume of blood in the upright posture. The effect, in turn, improves blood return to the heart and, therefore, functional capacity. In addition to its direct effect through extravascular fluid accumulation, fludrocortisone increases alpha1-adrenoreceptor sensitivity by about 50%. During therapy, the renin-angiotensin system is suppressed (as expected).
Clinical Context:
Midodrine is a prodrug with activity as an alpha1-adrenoreceptor agonist. This agent is widely used to treat orthostatic hypotension in MSA. Midodrine acts directly on the vasculature to increase BP and avoids electrolyte abnormalities associated with fludrocortisone. However, supine hypertension is a significant problem and limits the enhancement of functional capacity in MSA. Midodrine has often caused an unpleasant sensation in the scalp (due to piloerection).
Clinical Context:
Droxidopa is an oral norepinephrine precursor that is directly metabolized to norepinephrine by dopa-decarboxylase which is extensively distributed throughout the body. Peak droxidopa plasma concentrations are associated with increases in systolic and diastolic blood pressures. Droxidopa has no clinically significant effect on standing or supine heart rates in patients with autonomic failure. It is indicated for symptomatic neurogenic orthostatic hypotension (NOH) in patients with primary autonomic failure caused by diseases and conditions (eg, Parkinson disease, multiple system atrophy, and pure autonomic failure, dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy).
These agents augment coronary and cerebral blood flow. Agents such as ephedrine have been used in patients with MSA and share with midodrine the possible complication of excessive supine hypertension. The advantage of these short-acting vasopressors is that they can be given during the day if the patient does not lie down for 3-4 hours after taking them. A late-afternoon dose should be avoided if possible.
Clinical Context:
This is a recombinant EPO that has been shown to increase the functional capacity of patients with MSA, particularly those with characteristic mild anemia. Up to 38% of patients with severe autonomic failure have anemia. A lack of sympathetic stimulation may lead to decreased EPO production and anemia. Sympathetic impairment and low plasma norepinephrine levels are correlated with the severity of anemia.
Even low doses (25-50 U/kg SC 3 times weekly) of epoetin alfa have successfully corrected anemia and improved upright BP. The drug's biologic activity mimics that of human urinary EPO, which stimulates the division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the bloodstream.
These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclo-oxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.
Clinical Context:
Diphenhydramine is a first-generation antihistamine with anticholinergic effects that binds to H1 receptors in the CNS and body. It competitively blocks histamine from binding to H1 receptors.
Diphenhydramine affects structures in the neostriatum. It has significant antimuscarinic activity and penetrates the CNS, giving the drug a pronounced tendency to induce sedation. Approximately half of patients treated with conventional doses have some somnolence.
These agents prevent histamine response in sensory nerve endings and blood vessels. They are more effective in preventing histamine response than in reversing it.
What is multiple system atrophy (MSA)?How is multiple system atrophy (MSA) categorized?What is Shy-Drager syndrome?What are the clinical features of multiple system atrophy (MSA)?What are levels of certainty in the diagnosis of multiple system atrophy (MSA)?What are the signs and symptoms of multiple system atrophy (MSA)?Where can patient education resources for multiple system atrophy (MSA) be found?What is the pathophysiology of multiple system atrophy (MSA)?What is the prevalence of multiple system atrophy (MSA) in the US?What is the global prevalence rates of multiple system atrophy (MSA)?In which patient groups is multiple system atrophy (MSA) most prevalent?What is the prognosis of multiple system atrophy (MSA)?Which clinical history findings are characteristic of multiple system atrophy (MSA) in patients?What are the autonomic and urinary symptoms of multiple system atrophy (MSA)?What are indications of severe orthostatic hypotension in patients with multiple system atrophy (MSA)?Which symptoms are associated with orthostatic hypotension in multiple system atrophy (MSA)?What causes postprandial hypotension in multiple system atrophy (MSA)?What is the prevalence of supine hypertension in multiple system atrophy (MSA)?What are the features of parkinsonism in multiple system atrophy (MSA)?What are the signs and symptoms of cerebellar dysfunction in patients with multiple system atrophy (MSA)?How do the symptoms of multiple system atrophy (MSA) vary based on which system is involved?What is the prevalence of comorbid multiple system atrophy (MSA) and Parkinson disease?How is multiple system atrophy (MSA) differentiated from Parkinson disease?How is multiple system atrophy (MSA) differentiated from pure autonomic failure (PAF)?How is multiple system atrophy (MSA) differentiated from progressive supranuclear palsy (PSP)?How is multiple system atrophy (MSA) differentiated from corticobasal ganglionic degeneration?How is multiple system atrophy (MSA) differentiated from cerebrovascular syndromes?Which disorders should be included in the differential diagnoses of multiple system atrophy (MSA)?What are the differential diagnoses for Multiple System Atrophy?How is multiple system atrophy (MSA) diagnosed?What is the role of autonomic function testing in the workup of multiple system atrophy (MSA)?What is the role of sphincter electromyography (EMG) in the workup of multiple system atrophy (MSA)?How is incomplete bladder emptying assessed in the workup of multiple system atrophy (MSA)?What is the role of detrusor contraction testing in the workup of multiple system atrophy (MSA)?What is the role of scintigraphy in the workup of multiple system atrophy (MSA)?What is the role of MRI in the workup of multiple system atrophy (MSA)?Which MRI findings are characteristic of multiple system atrophy (MSA)?Which Trace (D) values on MRI suggest multiple system atrophy (MSA)?What is the role of positron emission tomography (PET) scanning in the workup of multiple system atrophy (MSA)?What are the histologic features of multiple system atrophy (MSA)?How is the progression of multiple system atrophy (MSA) reversed or halted?What are the nonpharmacologic treatments for multiple system atrophy (MSA)?What is the focus of pharmacologic therapy in the treatment of multiple system atrophy (MSA)?What is the role of surgery in the treatment of multiple system atrophy (MSA)?Which specialist consultations are beneficial for patients with multiple system atrophy (MSA)?Which diet modifications are used in the treatment of multiple system atrophy (MSA)?Which activity modifications are used in the treatment of multiple system atrophy (MSA)?How is orthostatic hypotension managed in multiple system atrophy (MSA)?How is postprandial hypotension managed in patients with multiple system atrophy (MSA)?How is supine hypertension managed in multiple system atrophy (MSA)?What is the role of pharmacologic therapy for multiple system atrophy (MSA)?Which medications are used to treat movement disorders in patients with multiple system atrophy (MSA)?Which medications are used to treat orthostatic hypotension in patients with multiple system atrophy (MSA)?Which medications are used in the treatment of supine hypertension in patients with multiple system atrophy (MSA)?Which medications in the drug class Antihistamines are used in the treatment of Multiple System Atrophy?Which medications in the drug class Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are used in the treatment of Multiple System Atrophy?Which medications in the drug class Hematopoietic Growth Factors are used in the treatment of Multiple System Atrophy?Which medications in the drug class Alpha/Beta Adrenergic Agonists are used in the treatment of Multiple System Atrophy?Which medications in the drug class Alpha1 Agonists are used in the treatment of Multiple System Atrophy?Which medications in the drug class Corticosteroids are used in the treatment of Multiple System Atrophy?Which medications in the drug class Agents for Erectile Dysfunction are used in the treatment of Multiple System Atrophy?Which medications in the drug class Prokinetic Agents are used in the treatment of Multiple System Atrophy?Which medications in the drug class Urinary Antispasmodic Agents are used in the treatment of Multiple System Atrophy?Which medications in the drug class Antiparkinson Agents, Anticholinergics are used in the treatment of Multiple System Atrophy?Which medications in the drug class Antiparkinson Agents, Dopamine Agonists are used in the treatment of Multiple System Atrophy?Which medications in the drug class Antiparkinson Agents, COMT Inhibitors are used in the treatment of Multiple System Atrophy?
André Diedrich, MD, PhD, Research Professor of Medicine, Adjunct Research Professor of Biomedical Engineering, Director of the Analytical and Phenotyping Core, Autonomic Dysfunction Center, Vanderbilt University School of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
David Robertson, MD, Director, Clinical and Translational Research Center, Vanderbilt Institute for Clinical and Translational Research, Principal Investigator, Autonomic Rare Disease Clinical Research Consortium, Elton Yates Professor of Medicine, Pharmacology, and Neurology, Vanderbilt University School of Medicine
Disclosure: Nothing to disclose.
Chief Editor
Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Ceribell, Eisai, Greenwich, Growhealthy, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion<br/>Serve(d) as a speaker or a member of a speakers bureau for: Eisai, Greenwich, LivaNova, Sunovion<br/>Received research grant from: Cavion, LivaNova, Greenwich, Sunovion, SK biopharmaceuticals, Takeda, UCB.
Acknowledgements
Nestor Galvez-Jimenez, MD, MSc, MHA Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society
Disclosure: Nothing to disclose.
Christopher Luzzio, MD Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison School of Medicine and Public Health
Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Introduction of the term olivopontocerebellar atrophy
Orthostatic hypotension (OH)
1925
Bradbury and Eggleston
Introduction of autonomic failure as a clinical syndrome
Shy-Drager syndrome (SDS)
1960
Shy and Drager
Origin of this term as a neuropathologic entity with parkinsonism and autonomic failure with OH
Striatonigral degeneration (SND)
1960
Van der Eecken et al
Description of SND
Multiple system atrophy (MSA)
1969
Graham and Oppenheimer
Introduction of the term MSA, which represents SDS, SND, and OPCA as 1 entity
Glial cytoplasmic inclusions (GCIs)
1989
Papp et al, Matsuo et al
Discovery of GCIs as hallmark of MSA
Alpha-synuclein inclusion
1998
Spillantini et al, Wakabayashi et al
Alpha-synuclein immunostaining as a sensitive marker of MSA
MSA classification
1996-1999
Consensus Committee
Classification of MSA based on clinical domains and features and neuropathology
Unified MSA Rating Scale (UMSARS)
2003
European MSA Study Group
Unified MSA Rating Scale as a standard to define MSA symptoms[4, 5]
Second consensus for MSA
2007
Consensus Committee
New definition of MSA with simplified criteria
Clinical Domain
Feature
Comment
Autonomic
dysfunction
Severe orthostatic hypotension (OH)
Asymptomatic
Symptomatic
OH is defined as blood pressure fall by at least 30mm Hg systolic and 15mm Hg diastolic within 3 minutes of standing from a previous 3-minute interval in the recumbent position.**
Urogenital dysfunction
Urinary incontinence (UI) or incomplete bladder emptying
UI is defined as persistent, involuntary, partial or total bladder emptying.
ED usually occurs before symptomatic OH.***
Erectile dysfunction (ED) in men
Parkinsonian features
(87% incidence *)
Bradykinesia (BK)
BK is slowness of voluntary movement with progressive reduction in speed and amplitude during repetitive actions.
PI not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction.
Rigidity
Postural instability (PI)
Tremor - Postural, resting, or both
Cerebellar dysfunction
(54% incidence *)
Gait ataxia (GA)
GA is a wide-based stance with steps of irregular length and direction.
Sustained gaze-evoked nystagmus
Ataxic dysarthria
Limb ataxia
Oculomotor dysfunction
Coritcospinal tract dysfunction
Extensor plantar response with hyperreflexia
Babinsky sign, Pyramidal sign
*Incidence of clinical features recorded during the lifetimes of 203 patients (Gilman et al[2] ).
**OH caused by drugs, food, temperature, deconditioning, or diabetes are excluded.
***ED does not count in the definition of onset of disease, because it is a general feature in older people.
Category
Additional Features
Possible
MSA-P
Possible
MSA-C
Babinski sign with hyperreflexia
Stridor
Possible
MSA-P
Rapidly progressive parkinsonism
Poor response to levodopa
Postural instability within 3 years of motor onset
Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction
Dysphagia within 5 years of motor onset
Atrophy on magnetic resonance imaging (MRI) of putamen, middle cerebellar peduncle, pons, or cerebellum
Hypometabolism on 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scanning in putamen, brainstem, or cerebellum
Possible
MSA-C
Parkinsonism (bradykinesia and rigidity)
Atrophy on MRI of the putamen, middle cerebellar peduncle, or pons
Hypometabolism on FDG-PET in the putamen
Presynaptic striatonigral dopaminergic denervation on single-photon emission computed tomography (SPECT) or PET scanning
*Modified from second consensus[6]
Procedure
Nonsupporting Features
History taking
Symptomatic onset at < 30 years
Onset after age 75 years
Family history of ataxia or parkinsonism
Systemic diseases or other identifiable causes for features listed in Table 2a
Hallucinations unrelated to medication
Dementia
Physical examination
Classic parkinsonian pill-rolling rest tremor
Clinically significant neuropathy
Prominent slowing of vertical saccades or vertical supranuclear gaze palsy
Evidence of focal cortical dysfunction, such as aphasia, alien limb syndrome, and parietal dysfunction
Laboratory study
Metabolic, molecular genetic, and imaging evidence of alternative cause of features listed in Table 2a
White matter lesions suggesting multiple sclerosis
Category
Definition
Possible MSA
A sporadic, progressive, adult (>30y) with onset disease* characterized by the following:
Parkinsonism or cerebellar syndrome
At least 1 feature of autonomic or urogenital dysfunction
At least 1 of the additional features from Table 2b
Probable MSA
A sporadic, progressive, adult (>30y) with onset disease* characterized by the following:
Autonomic failure involving urinary dysfunction
Poorly levodopa-responsive parkinsonism or cerebellar dysfunction
Definitive MSA
A sporadic, progressive, adult (>30y) with onset disease pathologically confirmed by presence of high density GCIs in association with degenerative changes in striatonigral and olivopontocerebellar pathways
*Disease onset is defined as the initial presentation of any parkinsonian or cerebellar motor problems or autonomic features (except erectile dysfunction).
Clinical Symptom
Pathologic Findings and Location of Damage or Cell Loss
Orthostatic hypotension
Primary preganglionic damage of intermediolateral cell columns
Urinary incontinence (not retention)
Preganglionic cell loss in spinal cord (intermediolateral cell columns), related to detrusor hyperreflexia caused mainly by loss of inhibitory input to pontine micturition center (rather than to external urethral sphincter denervation alone)
Urinary retention caused by detrusor atonia
Sacral intermediolateral cell columns
Cerebellar ataxia
Cell loss in inferior olives, pontine nuclei, and cerebellar cortex
Pyramidal signs
Pyramidal tract demyelination
Extensor plantar response
Pyramidal tract lesion
Hyperreflexia
Pyramidal tract lesion
Motor abnormalities
GCIs in cortical motor areas or basal ganglia
Akinesia
Putamen, globus pallidus
Rigidity
Putaminal (not nigral) damage
Limb and gait ataxia
Inferior olives, basis pontis
Decreased or absent levodopa responsiveness
Striatal cell loss, loss of D1 and D2 receptors in striatum or impaired functional coupling of D1 and D2 receptors
Nystagmus
Inferior olives, pontine nuclei
Dysarthria
Pontine nuclei
Laryngeal stridor
Severe cell loss in nucleus ambiguus or biochemical defect causing atrophy of posterior cricoarytenoid muscles
Excessive daytime sleepiness
Loss of putative wake-active ventral periaqueductal gray matter dopaminergic neurons[13]
Adapted from Wenning et al and other sources.
Characteristic
MSA
Parkinson Disease
Response to chronic levodopa therapy*
Poor or unsustained motor response because of loss of postsynaptic dopamine receptors
Initial improvement in 30% of patients with MSA, but 90% were unresponsive over a longer time; 50% develop levodopa-induced dyskinesia of orofacial and neck muscles
Good response
Effects on striatonigral transmission
Presynaptic and postsynaptic; dopaminergic cell bodies in substantia nigra and their terminals in striatum, as well as their striatal target cells, have reduced dopamine receptors
Presynaptic
Symmetry of movement disorder
Possibly asymmetrical
No data
Progression of symptoms
Rapid
Slow
Postural instability and falling**
Early
Fast progression
Worsen >20% of UPDRS scale**
Late
Less progression (< 10%)
Progress of disability
Relatively fast disability; 30% decrease of activities of daily living in 1 year; 40% of patients in a wheelchair within 5 years (wheel chair sign)
Relatively slow disability
Abnormal speech
Severely affected speech in 30% of patients with MSA
Dysarthrophonia and severe dysarthria are common
Less affected
Abnormal Respiration
Abnormal aspiration, inspiratory gasps, and stridor in 60% of patients with MSA
Stridor caused by paralysis of vocal cord occurs especially at night but is also present during day
Cytoplasmic inclusions (immunocytochemical reaction with antibodies to alpha synuclein)
Glial inclusions; argyrophilic cellular inclusions in oligodendrocytes
Absent
Thermoregulation, skin perfusion
Cold hands and decrease of warm-up after cold-pack stimulus
Normal
Caudate-putamen index of dopamine uptake (on positron emission tomography [PET] scanning)
Decreased in putamen and caudate
Decreased in putamen with smaller decrease in caudate
Growth hormone release with intravenous (IV) injection of clonidine
No release; dysfunction of hypothalamic-pituitary pathway (alpha2-adrenoceptor-hypothalamic deficit)
Increase of growth hormone, intact function
* A positive response to levodopa is defined as a significant improvement of motor features during 3 months’ application of escalating doses of levodopa with a peripheral decarboxylase inhibitor.[6]
** Postural instability as defined by item 30 of the Unified Parkinson's Disease Rating Scale (UPDRS) part III (motor examination).[6]
*** Pakiam et al reported that patients with diffuse Lewy-body disease may present with parkinsonism and prominent autonomic dysfunction, fulfilling some proposed criteria for the striatonigral form of MSA.[27]
Mineralocorticoid; sodium retention, primarily in extravascular compartment, causes tissue edema to venous capacitance bed in lower extremity. With this edema, venous bed accommodates decreased volume of blood in an upright posture (high doses, late effect); increases sensitivity to norepinephrine (even with small doses)
Sympathomimetic amines
Midodrine
Alpha1-adrenoreceptor agonist acts directly on vasculature, causes venous and arteriolar vasoconstriction
Droxidopa
Droxidopa is a synthetic precursor of norepinephrine. It acts by conversion to norepinephrine in the body.
Recombinant erythropoietin (EPO)
Epoetin alfa
Increases sensitivity to pressor effects of angiotensin II; increases plasma endothelin level; increases cytosolic free calcium in vascular smooth muscle; increases intravascular volume
NSAIDs
Indomethacin, ibuprofen
Inhibition of vasodilator prostaglandins proposed but not proven
Antihistamines
Diphenhydramine, cimetidine
Reduce vasodilatation caused by histamine release
Somatostatin analogs
Octreotide
Reduce splanchnic capacitance
Vasopressin agonists
Desmopressin (DDAVP)
Vasopressin analogs; no effect on V1 receptors, which are responsible for vasopressin-induced vasoconstriction; acts on V2 receptors on renal tubuli, which are responsible for antidiuretic effect; prevents nocturnal diuresis, raises BP in morning
